mTORC1 controls glycogen synthase kinase 3β nuclear localization and function
| Autor: | Christopher M. Yip, Costin N. Antonescu, Noa Mecica, Peter K. Kim, Adriano Vissa, Ivan Boras, Stephen Bautista |
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| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
biology Endosome Chemistry AMPK mTORC1 Cell biology 03 medical and health sciences 0302 clinical medicine GSK-3 biology.protein Endomembrane system biological phenomena cell phenomena and immunity Protein kinase A Mechanistic target of rapamycin 030217 neurology & neurosurgery Nuclear localization sequence 030304 developmental biology |
| Popis: | Glycogen synthase kinase 3β (GSK3β) phosphorylates and regulates a wide range of substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-myc and snail, are nuclear-resident transcription factors, suggesting possible control of GSK3β function by regulation of its nuclear localization. Inhibition of mechanistic target of rapamycin (mTORC1) led to partial redistribution of GSK3β from the cytosol to the nucleus, and GSK3β-dependent reduction of the expression of c-myc and snail. mTORC1 is controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance. Indeed AMPK activation or amino acid deprivation promoted GSK3β nuclear localization in an mTORC1-dependent manner. GSK3β was detected in several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through perturbation of Rab7 resulted in loss of GSK3β from lysosomes, and enhanced GSK3β nuclear localization as well as GSK3β-dependent reduction of c-myc levels. This indicates that GSK3β nuclear localization and function is suppressed by mTORC1, and suggests a new link between metabolic conditions sensed by mTORC1 and GSK3β-dependent regulation of transcriptional networks controlling biomass production.Summary statement (15-30 words)GSK3β nuclear localization and function is negatively regulated by the metabolic and mitogenic sensor mTORC1. mTORC1 control of GSK3β localization requires Rab7 and lysosomal membrane traffic. |
| Databáze: | OpenAIRE |
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